Cylodextrin Complexation Methods for Formulating Peptide Proteasome Inhibitors

Abstract

This disclosure provides methods for formulating compositions comprising one or more peptide proteasome inhibitors and a cyclodextrin, particularly a substituted cyclodextrin. Such methods substantially increase the solubility and stability of these proteasome inhibitors and facilitate both their manufacture and administration.

1 . A method for preparing a pharmaceutical composition, the method comprising:
 (i) providing a first combination comprising:
 (a) a compound: 
   
       
         
           
           
               
               
           
         
         
           or a pharmaceutically acceptable salt thereof; 
           (b) one or more cyclodextrins (“CDs”); and 
           (c) water;
 wherein the first combination is heterogeneous and the compound or salt has a low solubility in the first combination; and 
 
         
         (ii) contacting the first combination with an acid to form a second combination, wherein the compound is more soluble in the second combination than in the first combination. 
       
     
     
         2 . The method of  claim 1 , wherein the first combination is substantially free of organic solvent. 
     
     
         3 . The method of  claim 1 , wherein the first combination is substantially free of buffer. 
     
     
         4 . The method of  claim 1 , wherein the second combination comprises a complex of the compound and the one or more cyclodextrins. 
     
     
         5 . The method of  claim 1 , wherein the acid is added in the form of an aqueous solution. 
     
     
         6 . The method of  claim 1 , wherein at least one of the one or more cyclodextrins is HPBCD or SBECD. 
     
     
         7 . The method of  claim 1 , wherein at least one of the one or more cyclodextrins is a low chloride cyclodextrin. 
     
     
         8 . The method of  claim 7 , wherein the low chloride cyclodextrin is a low chloride SBECD. 
     
     
         9 . The method of  claim 1 , wherein the mole ratio of chloride ion to compound in the first combination is not more than 0.32. 
     
     
         10 . The method of  claim 1 , wherein providing a first combination (step (i)) comprises adding the compound to a solution of the one or more cyclodextrins and the water. 
     
     
         11 . The method of  claim 10 , wherein the compound is a crystalline solid. 
     
     
         12 . The method of  claim 11 , wherein the crystalline form of the compound has an X-ray powder diffraction pattern comprising 2 to 8 characteristic peaks expressed in degrees 2θ at 6.10, 9.32, 10.10, 12.14, 13.94, 18.44, 20.38, and 23.30. 
     
     
         13 . The method of  claim 1 , wherein the method further comprises mixing the first combination prior to contacting the first combination with an acid. 
     
     
         14 . The method of  claim 1 , wherein (i) and (ii) are both performed in a single vessel. 
     
     
         15 . The method of  claim 1 , wherein method further comprises mixing the second combination for a time sufficient to achieve a homogeneous third combination. 
     
     
         16 . The method of  claim 15 , wherein the dissolved and complexed concentration of the compound in the third combination is from 1 mg/mL to 20 mg/mL. 
     
     
         17 . The method of  claim 16 , wherein the dissolved and complexed concentration of the compound in the third combination is from 4 to 8 mg/mL. 
     
     
         18 . The method of  claim 15 , wherein the pH of the third combination is from 2 to 4. 
     
     
         19 . The method of  claim 15 , wherein the method further comprises filtering the third combination. 
     
     
         20 . The method of  claim 15 , wherein the method further comprises lyophilizing the third combination to provide a lyophilizate. 
     
     
         21 . The method of  claim 20 , wherein the method further comprises mixing the lyophilizate with a pharmaceutically acceptable carrier. 
     
     
         22 . The method of  claim 21 , wherein the pharmaceutically acceptable carrier comprises sterile water for injection. 
     
     
         23 . The method of  claim 22 , wherein the pharmaceutically acceptable carrier further comprises citric acid. 
     
     
         24 . A pharmaceutical composition prepared by a method comprising:
 (i) providing a first combination comprising:
 (a) a compound: 
   
       
         
           
           
               
               
           
         
         
           or a pharmaceutically acceptable salt thereof; 
           (b) one or more cyclodextrins (“CDs”); 
           (c) water; and 
           (d) chloride ion;
 wherein the first combination is heterogeneous, and the compound or salt has a low solubility in the first combination; and 
 
         
         (ii) contacting the first combination with an acid to form a second combination, wherein the compound is more soluble in the second combination than in the first combination; and
 wherein each of the first and second combinations independently has a chloride ion concentration of from 0.01 to 0.05% (w/v). 
 
       
     
     
         25 . The pharmaceutical composition of  claim 24 , wherein each of the first and second combinations has a chloride ion concentration of from 0.01 to 0.03% (w/v). 
     
     
         26 . The pharmaceutical composition of  claim 25 , wherein at least one of one or more cyclodextrins is sulfobutyl ether beta-cyclodextrin (“SBECD”). 
     
     
         27 . The pharmaceutical composition of  claim 24 , wherein the mole ratio of chloride ion to compound in the first combination is from 0.2 to 1.2. 
     
     
         28 . The pharmaceutical composition of  claim 24 , wherein the method further comprises: mixing the second combination for a time sufficient to achieve a homogeneous third combination; and lyophilizing the third combination to provide a lyophilizate. 
     
     
         29 . The pharmaceutical composition of  claim 28 , wherein the lyophilizate contains less than 0.1% by HPLC of chlorohydrin degradation product after storage for six months at 5° C. 
     
     
         30 . The pharmaceutical composition of  claim 28 , wherein the mole ratio of chloride ion to compound in the third combination is from 0.2 to 0.4.